N-heterocyclic methylpropylamine derivatives, process for producing the same and germicides

ABSTRACT

N-heterocyclicmethylpropylamine derivatives of formula (I):and acid addition salts thereof;wherein R1 represents hydrogen, halogen, alkyl, alkenyl, halogenated alkyl, alkoxy, halogenated alkoxy, hydroxyl, cyano, nitro, phenyl optionally having a substituent on a ring thereof or phenoxy; n represents an integer of 0-5; R2 represents a heterocycle containing at least one nitrogen atom as the hetero atom and optionally having a substituent on a ring thereof; and R3 represents hydrogen or C1-C5 alkyl.

TECHNICAL FIELD

This invention relates to novel propylamine derivatives havingphysiological activities, and particularly it relates to novelN-heterocyclicmethylpropylamine derivatives that can be utilized as theeffective ingredients of fungicides (such as those for use in farmingand horticulture).

BACKGROUND ART

Commercially available fungicides include, as 3-phenylpropylamines,N-[3-p-t-butylphenyl-2-methyl-1-propyl]-cis-2,6-dimethylmorpholine(fenpropimorph), a compound described in Japanese Unexamined PatentPublication No. SHO 53-77070, andN-[3-p-t-butylphenyl-2-methyl-1-propyl]piperidine (fenpropidine), acompound described in Japanese Unexamined Patent Publication No. SHO53-68785 and No. SHO 53-68786.

The nitrogen atom of the amino group in each of the aforementionedcompounds forms part of a ring. In contrast, the only compounds knownwherein the nitrogen atom of the amino group does not form part of aring and a heterocyclicmethyl group is bonded to the nitrogen atom, arethose with a tetrahydrofurfuryl group as described in JapaneseUnexamined Patent Publication No. SHO 63-258867, those withheterocyclicmethyl groups containing oxygen or sulfur, such as thenyl,and the following compounds listed in Pestic. Sci., 35, 339 (1992):

N-[3-(4-t-butylphenyl)-2-methylpropyl]-N-(t-butyl)-3-pyridylmethylamine;

N-[3-(4-t-butylphenyl)-2-methylpropyl]-N-butyl-3-pyridylmethylamine; and

N-[3-(4-t-butylphenyl)-2-methylpropyl]-N-methyl-3-pyridylmethylamine.

DISCLOSURE OF THE INVENTION

However, except for the aforementioned compounds having a3-pyridylmethyl group, no compounds are known wherein a heterocyclecontaining at least one nitrogen atom as the hetero atom and having anoptional substituent on the ring is bonded to the nitrogen atom of theamino group via methylene, such as in theN-heterocyclicmethylpropylamine derivatives represented by the followingformula (I):

Moreover, no compounds with substituents on the heterocycle have yetbeen reported, and consequently no studies have yet been conducted onthe usefulness of such compounds.

It is an object of this invention to provide a novelN-heterocyclicmethylpropylamine derivative that is useful as aphysiologically active substance in a fungicide, for example. It isanother object of the invention to provide a process for preparation ofthe N-heterocyclicmethylpropylamine derivatives described above andutility therefor.

According to this invention, there is provided aN-heterocyclicmethylpropylamine derivative of formula (I):

or an acid addition salt thereof;

wherein R¹ represents at least one moiety selected from the groupconsisting of hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆halogenated alkyl, C₁-C₆ alkoxy, C₁-C₆ halogenated alkoxy, hydroxyl,cyano, nitro, phenyl optionally having a substituent on a ring thereofand phenoxy; n represents an integer of 0-5; when n is 2 or greater,each R¹ may be the same or different and two R¹ groups may be bondedtogether into a ring or crosslinked; R² represents a heterocyclecontaining at least one nitrogen atom as the hetero atom and optionallyhaving a substituent on a ring thereof; and R³ represents at least onemoiety selected from the group consisting of hydrogen and C₁-C₅ alkyl,

with the proviso that the following compounds are excluded:

N-[3-(4-t-butylphenyl)-2-methylpropyl]-N-(t-butyl)-3-pyridylmethylamine,

N-[3-(4-t-butylphenyl)-2-methylpropyl]-N-butyl-3-pyridylmethylamine, and

N-[3-(4-t-butylphenyl)-2-methylpropyl]-N-methyl-3-pyridylmethylamine.

Optical isomers may exist for the N-heterocyclicmethylpropylaminederivative of formula (I) of the invention as described above, becausethere is an asymmetric carbon at the 2-position of its propyl group,regardless of any asymmetry due to other substituents. Consequently, acompound of formula (I) of the invention naturally encompasses either ofsingle optical isomers and any mixtures of the optical isomers.

According to the invention, there is also provided a process forpreparation comprising reductive amination between a3-phenylpropionaldehyde derivative of formula (II) and aheterocyclicmethylamine derivative of formula (III) to obtain anN-heterocyclicmethylpropylamine derivative of formula (I):

(in formulae (I), (II) and (III) R¹, R², R³ and n are as previouslydefined).

According to the invention, reductive amination may be employed tosynthesize a 3-phenylpropylamine derivative of formula (IV) from a3-phenylpropionaldehyde derivative of formula (II) and an aminatingagent of formula (VIII) or, alternatively, a 3-phenylpropionamidederivative of formula (XII) may be reduced to synthesize a3-phenylpropylamine derivative of formula (IV); and anN-heterocyclicmethylpropylamine derivative of formula (I) is synthesizedfrom this compound (IV) and a heterocycle-methylating agent of formula(V). On the other hand, reductive amination may also be used tosynthesize an N-heterocyclicmethylpropylamine derivative of formula (I)from a compound of (IV) and a heterocyclicaldehyde derivative of formula(VI):

(in the above formulae R¹, R², R³ and n are as previously defined, and Xrepresents a leaving group).

BEST MODE FOR CARRYING OUT THE INVENTION

This invention will be explained in greater detail hereinbelow.

N-heterocyclicmethylpropylamine Derivatives

In the N-heterocyclicmethylpropylamine derivatives of formula (I) above,R¹ represents at least one moiety selected from the group consisting ofhydrogen, halogen, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ halogenated alkyl,C₁-C₆ alkoxy, C₁-C₆ halogenated alkoxy, hydroxyl, cyano, nitro, phenyloptionally having a substituent on a ring thereof, and phenoxy. Thehalogen atom may be fluorine, chlorine, bromine or iodine. The alkylportion of the C₁-C₆ alkyl, C₁-C₆ halogenated alkyl, C₁-C₆ alkoxy orC₁-C₆ halogenated alkoxy group may be primary, secondary or tertiary.

Among these groups for R¹ preferred are halogen atoms, halogenatedalkyl, halogenated alkoxy and tertiary alkyl groups, examples of whichinclude chlorine, fluorine and bromine atoms, and trifluoromethyl,trifluoromethoxy and 1,1-dimethylethyl (equivalent to t-butyl) groups.The position of substitution on the phenyl ring of R¹ is notparticularly limited, but the 3-position and 4-position are preferred.

“n” represents an integer of 0-5, and n is preferably 1 or 2. When n is2 or greater, each R¹ may be the same or different. Also, two R¹ groupsmay be bonded together into a ring or crosslinked, and for example, theymay together with the benzene ring form indane,1,2-methylenedioxybenzene or naphthalene.

R² represents a heterocycle containing at least one nitrogen atom as thehetero atom and optionally having a substituent on a ring thereof. Thisheterocycle R² contains at least one nitrogen atom as the hetero atom,although it may also have one or more other hetero atoms (oxygen,sulfur, etc.), and the heterocycle R² is preferably a 5- or 6-memberedring. As specific preferred examples of the heterocycle R² there may bementioned pyridine, pyrazine, pyrimidine, thiazole, oxazole, pyrazoleand pyrrole.

As a substituent on the heterocycle, there may be mentioned halogen(which may be fluorine, chlorine, bromine or iodine), alkyl (among whicha C₁-C₄ alkyl group is preferred, and methyl, ethyl or 1-methylethyl isparticularly preferred), halogenated alkyl (a group wherein at least oneof the hydrogen atoms of the alkyl group is substituted with a halogenatom: fluorine is preferred as the halogen atom and C₁-C₄ alkyl as thenumber of carbon atoms, with trifluoromethyl being particularlypreferred), alkoxy (among which a C₁-C₄ alkoxy group is preferred, andmethoxy is particularly preferred), a di(C₁-C₄ alkyl)amino group andnitro. The number of substituents is not particularly limited, but ispreferably 1 or 2. When two or more substituents are bonded to theheterocycle, they may be the same or different.

R³ represents at least one moiety selected from the group consisting ofhydrogen and C₁-C₅ alkyl, and it is preferably methyl. Methyl is alsopreferred in the definition of R⁴ (C₁-C₅ alkyl group) given hereunder.

Preferred Combinations

The compounds of formula (I) comprising the preferred combinations ofR¹, R², R³ and n as described above are the preferred compounds in thisinvention; for example, the following compounds listed in Tables 1-9 maybe mentioned as such.

TABLE 1 R² R³ compound no. (R¹)n I-1 2-pyridyl methyl4-(1,1-dimethylethyl) I-2 4-pyridyl methyl 4-(1,1-dimethylethyl) I-36-chloro-3-pyridyl hydrogen 4-(1,1-dimethylethyl) I-4 6-chloro-3-pyridylmethyl 4-(1,1-dimethylethyl) I-5 6-bromo-3-pyridyl methyl4-(1,1-dimethylethyl) I-6 6-fluoro-3-pyridyl methyl4-(1,1-dimethylethyl) I-7 6-methyl-3-pyridyl methyl4-(1,1-dimethylethyl) I-8 6-trifluoromethyl-3-pyridyl methyl4-(1,1-dimethylethyl) I-9 6-methoxy-3-pyridyl methyl4-(1,1-dimethylethyl)  I-10 2-chloro-3-pyridyl methyl4-(1,1-dimethylethyl)  I-11 2,6-dichloro-3-pyridyl methyl4-(1,1-dimethylethyl)

TABLE 2 R² R³ compound no. (R¹)n I-12 5-chloro-2-pyrazyl methyl4-(1,1-dimethylethyl) I-13 5-methyl-2-pyrazyl methyl4-(1,1-dimethylethyl) I-14 5-chloro-6-methyl-2-pyrazyl methyl4-(1,1-dimethylethyl) I-15 1-methyl-2-imidazolyl methyl4-(1,1-dimethylethyl) I-16 6-chloro-3-pyridazyl methyl4-(1,1-dimethylethyl) I-17 1-methyl-1H-pyrazol-4-yl methyl4-(1,1-dimethylethyl) I-18 1,3-dimethyl-1H-pyrazol-4-yl methyl4-(1,1-dimethylethyl) I-19 5-chloro-1-methyl-1H-pyrazol-4-yl methyl4-(1,1-dimethylethyl) I-20 1,3,5-trimethyl-1H-pyrazol-4-yl methyl4-(1,1-dimethylethyl) I-21 2-chloro-5-thiazolyl methyl4-(1,1-dimethylethyl) I-22 5-isoxazolyl methyl 4-(1,1-dimethylethyl)

TABLE 3 R² R³ compound no. (R¹)n I-23 6-chloro-3-pyridyl methyl 2-chloroI-24 6-chloro-3-pyridyl methyl 4-chloro I-25 6-chloro-3-pyridyl methyl2,4-dichloro I-26 6-chloro-2-pyridyl methyl 4-(1,1-dimethylethyl) I-276-chloro-3-pyridyl ethyl 4-(1,1-dimethylethyl) I-28 6-chloro-3-pyridyl1-methylethyl 4-(1,1-dimethylethyl) I-29 4-chloro-2-pyridyl methyl4-(1,1-dimethylethyl) I-30 1-ethyl-1H-pyrazol-4-yl methyl4-(1,1-dimethylethyl) I-31 6-chloro-3-pyridyl 1,1-dimethylethyl4-(1,1-dimethylethyl) I-32 2-methyl-5-pyrimidyl methyl4-(1,1-dimethylethyl) I-33 2,6-dichloro-5-pyrimidyl methyl4-(1,1-dimethylethyl)

TABLE 4 R² R³ compound no. (R¹)n I-34 2-methoxy-5-pyrimidyl methyl4-(1,1-dimethylethyl) I-35 2-methylthio-5-pyrimidyl methyl4-(1,1-dimethylethyl) I-36 2-pyrrolyl methyl 4-(1,1-dimethylethyl) I-371-methyl-2-pyrrolyl methyl 4-(1,1-dimethylethyl) I-38 6-chloro-3-pyridylmethyl 3-chloro I-39 6-chloro-3-pyridyl methyl 2-methyl I-406-chloro-3-pyridyl methyl 2,6-dichloro I-41 6-chloro-3-pyridyl methyl2-methoxy I-42 6-chloro-3-pyridyl methyl 2-trifluoromethyl I-436-chloro-3-pyridyl methyl 2,4-dimethyl I-44 6-chloro-3-pyridyl methyl2-fluoro

TABLE 5 R² R³ compound no. (R¹)n I-45 6-chloro-3-pyridyl methyl 2-bromoI-46 6-chloro-3-pyridyl methyl 4-methyl I-47 6-chloro-3-pyridyl methyl4-isopropyl I-48 6-chloro-3-pyridyl methyl 3-trifluoromethyl I-496-chloro-3-pyridyl methyl 3-trifluoromethoxy I-50 6-chloro-3-pyridylmethyl 3-iodo I-51 6-chloro-3-pyridyl methyl 3-isopropyloxy I-526-chloro-3-pyridyl methyl 3-nitro I-53 6-chloro-3-pyridyl methyl3-hydroxy I-54 6-chloro-3-pyridyl methyl 3,4-dichloro I-556-chloro-3-pyridyl methyl 2,5-dichloro

TABLE 6 R² R³ compound no. (R¹)n I-56 6-chloro-3-pyridyl methyl2,3-dichloro I-57 6-chloro-3-pyridyl methyl 3,5-dichloro I-586-chloro-3-pyridyl methyl 3,5-dimethoxy I-59 6-chloro-3-pyridyl methyl3-chloro, 4-methoxy I-60 6-chloro-3-pyridyl methyl 3-chloro, 4-hydroxyI-61 6-chloro-3-pyridyl methyl hydrogen I-62 6-chloro-3-pyridyl methyl4-fluoro I-63 6-chloro-3-pyridyl methyl 4-trifluoromethyl I-646-chloro-3-pyridyl methyl 3,4-difluoro I-65 6-chloro-3-pyridyl methyl3-bromo I-66 6-chloro-3-pyridyl methyl 3-methyl

TABLE 7 R¹ R³ compound no. (R¹)n I-67 6-chloro-3-pyridyl methyl 3-cyanoI-68 6-chloro-3-pyridyl methyl 3-phenoxy I-69 6-chloro-3-pyridyl methyl3-(1,1-dimethylethyl) I-70 6-chloro-3-pyridyl methyl 3-chloro, 4-fluoroI-71 6-chloro-3-pyridyl methyl 3-methyl, 4-nitro I-72 6-chloro-3-pyridylmethyl 3-methoxy, 4-chloro I-73 6-chloro-3-pyridyl methyl 3-hydroxy,4-chloro I-74 6-chloro-3-pyridyl methyl 3,5-dimethyl I-756-chloro-3-pyridyl methyl 3-fluoro I-76 6-chloro-3-pyridyl methyl3-methoxy I-77 6-chloro-3-pyridyl methyl 3-vinyl

TABLE 8 R² R³ compound no. (R¹)n I-78 6-chloro-3-pyridyl methyl 3-phenylI-79 6-chloro-3-pyridyl methyl 4-phenyl I-80 6-chloro-3-pyridyl methyl3,4-dimethyl I-81 6-chloro-3-pyridyl methyl 2-chloro, 5-trifluoromethylI-82 6-chloro-3-pyridyl methyl 3-chloro, 4-methyl I-836-chloro-3-pyridyl methyl 3-bromo, 4-fluoro I-84 6-chloro-3-pyridylmethyl 3-trifluoromethyl, 4-fluoro I-85 6-chloro-3-pyridyl methyl3,4-dibromo I-86 6-chloro-3-pyridyl methyl 3-fluoro, 4-chloro I-876-chloro-3-pyridyl methyl 3-(2,2,2-trifluoroethoxy) I-886-chloro-3-pyridyl methyl 3-(1,1,2,2-tetrafluoroethoxy)

TABLE 9 R² R³ compound no. (R¹)n I-89 6-chloro-3-pyridyl methyl3-trifluoromethyl, 4-chloro I-90 6-chloro-3-pyridyl methyl indan-5-yl *)I-91 6-chloro-3-pyridyl methyl 3,4-methylenedioxyphenyl *) I-926-chloro-3-pyridyl methyl naphthalen-2-yl *) *): (R¹)n forms a ringtogether with the benzene ring.

Process for the Preparation of Propylamine Derivatives

Preferably, the N-heterocyclicmethylpropylamine derivatives of formula(I) as described above can be prepared by Route A or Route B as shownbelow.

(in the above formulae R¹ represents a moiety selected from the groupconsisting of hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆halogenated alkyl, C₁-C₆ alkoxy, C₁-C₆ halogenated alkoxy, hydroxyl,cyano, nitro, phenyl optionally having a substituent on a ring thereofand phenoxy; n represents an integer of 0-5; when n is 2 or greater,each R¹ may be the same or different and two R¹ groups may be bondedtogether into a ring or crosslinked; R² represents a heterocyclecontaining at least one nitrogen atom as the hetero atom and optionallyhaving a substituent on a ring thereof; R³ represents at least onemoiety selected from the group consisting of hydrogen and C₁-C₅ alkyl;and X represents a leaving group).

(Route A)

Employing reductive amination, a 3-phenylpropionaldehyde derivative offormula (II) is allowed to react with a heterocyclicmethylaminederivative of formula (III) in the presence of a reducing agent tosynthesize an N-heterocyclicmethylpropylamine derivative of formula (I).

(Route B)

The nitrogen atom of the amino group of a 3-phenylpropylamine derivativeof formula (IV) may be alkylated with a heterocycle-methylating agent offormula (V) to synthesize an N-heterocyclicmethylpropylamine derivativeof formula (I) (Route B-1); or alternatively, reductive amination may beemployed to synthesize an N-heterocyclicmethylpropylamine derivative offormula (I) by allowing a compound of formula (IV) to react with aheterocyclicaldehyde derivative of formula (VI) in the presence of areducing agent (Route B-2).

(in formulae (I-a), (I-b) and (VII) R¹, R³, n and X are as previouslydefined, and R⁴ represents C₁-C₅ alkyl).

As shown in reaction scheme (C) above, the nitrogen atom of the aminogroup of an N-heterocyclicmethylpropylamine derivative of formula (I-a)[a secondary amine equivalent to compound (I) wherein R³=H] may bealkylated with a C₁-C₅ alkylating agent of formula (VII) to synthesizean N-alkyl-N-heterocyclicmethylpropylamine derivative of formula (I-b)[equivalent to compound (I) wherein R³=C₁-C₅ alkyl].

(Starting Materials)

Several commercially available 3-phenylpropionaldehyde derivatives offormula (II) may be used as starting materials. Compounds (II) can besynthesized by the reaction shown below, referring to the methoddescribed in Tetrahedron Letters, 8, 597(1976).

[Synthetic Schemes (1), (2)]

Synthetic Routes to 3-phenylpropylamine Derivatives

(in the above formulae R¹, R³ and n are as previously defined, and R⁵and R⁶ each independently represent C₁-C₄ alkyl).

A 3-phenylpropylamine derivative of formula (IV) may be obtained from a3-phenylpropionaldehyde derivative of formula (II) and an aminatingagent of formula (VIII) in the presence of a reducing agent, by usingreductive amination such as that shown in synthetic schemes (1) and (2)above.

A 3-phenylpropylamine derivative of formula (IV) may also be prepared byusing a methylmalonic acid diester (IX) (wherein R⁵ and R⁶ eachindependently represent C₁-C₄ alkyl) as the starting material, reactingit with a benzyl compound (XIII) in the presence of a base to produce abenzyl derivative (X); hydrolyzing and decarboxylating the benzylderivative (X) to produce a carboxylic acid derivative (XI); convertingthe carboxylic acid derivative (XI) to a 3-phenylpropionamide derivative(XII) by the use of an aminating agent of formula (VIII); and thenreducing compound (XII) with aluminum lithium hydride to obtain compound(IV).

The other starting compounds to be used in the invention includeheterocyclicmethylamine derivatives of formula (III), aminating agentsof formula (VIII), heterocycle-methylating agents of formula (V), C₁-C₅alkylating agents of formula (VII), benzyl compounds of formula (XIII),heterocyclicaldehyde derivatives of formula (VI) and methylmalonic aciddiesters of formula (IX).

Some of these compounds are described in the literature: see, forexample, J. Heterocyclic. Chem., 5, 407 (1968); ibid., 6, 549 (1969); J.Org. Chem., 21, 97 (1956); Japanese Unexamined Patent Publication SHONo. 59-59669; Japanese Unexamined Patent Publication HEI No. 2-171;Aust. J. Chem., 21, 2251 (1974); and Chem. Pharm. Bull., 28 3057 (1980).Several of these compounds that are commercially available may also beused. They can also be synthesized utilizing the methods described inthe literature, including those cited above.

(Amines)

The following compounds may be mentioned as a heterocyclicmethylaminederivative of formula (III): 2-pyridylmethylamine, 4-pyridylmethylamine,6-chloro-3-pyridylmethylamine, 6-chloro-N-methyl-3-pyridylmethylamine,6-fluoro-3-pyridylmethylamine, 6-fluoro-N-methyl-3-pyridylmethylamine,5-chloro-2-pyrazylmethylamine, 5-chloro-N-methyl-2-pyrazylmethylamine,2-chloro-3-pyridylmethylamine, 2-chloro-N-methyl-3-pyridylmethylamine,2-chloro-5-thiazolylmethylamine, and2-chloro-N-methyl-5-thiazolylmethylamine.

The following compounds may be mentioned as an aminating agent offormula (VIII): ammonia, methylamine, ethylamine, propylamine,isopropylamine, butylamine, isobutylamine, sec-butylamine, t-butylamine,pentylamine, and isopentylamine.

(Alkylating Agents)

The following compounds may be mentioned as a heterocycle-methylatingagent of formula (V): 2-chloromethylpyridine, 4-chloromethylpyridine,6-chloro-3-chloromethylpyridine, 6-bromo-3-bromomethylpyridine,3-bromomethyl-6-fluoropyridine, 3-chloromethyl-6-methylpyridine,3-bromomethyl-6-trifluoromethylpyridine,3-bromomethyl-6-methoxypyridine, 2-chloro-3-chloromethylpyridine,6-chloro-2-chloromethylpyridine, 4-chloro-2-chloromethylpyridine,2,6-dichloro-3-chloromethylpyridine, 5-chloro-2-chloromethylpyrazine,5-methyl-2-chloromethylpyrazine,5-chloro-2-chloromethyl-6-methylpyrazine, 4-chloromethylpyrimidine,2-chloro-5-chloromethylpyrimidine, 3-chloro-6-chloromethylpyridazine,2-chloro-5-chloromethylthiazole, 5-bromomethylisoxazole,5-chloro-4-chloromethyl-1-methylpyrazole,6-chloro-2-chloromethylpyridine, 4-chloro-2-chloromethylpyridine, and2,6-dichloro-5-bromomethylpyrimidine.

The following compounds may be mentioned as a C₁-C₅ alkylating agent offormula (VII): methyl iodide, methyl bromide, ethyl bromide, ethyliodide, isopropyl bromide, isopropyl iodide, butyl iodide, isobutyliodide, sec-butyl iodide, pentyl iodide, isopentyl iodide, dimethylsulfate, diethyl sulfate, and methyl p-toluenesulfonate.

The following compounds may be mentioned as a benzyl compound of formula(XIII): 2-chlorobenzyl chloride, 3-chlorobenzyl chloride, 4-chlorobenzylchloride, 2-methylbenzyl chloride, 3-methylbenzyl chloride,4-methylbenzyl chloride, 2-methoxybenzyl chloride, 3-methoxybenzylchloride, 4-methoxybenzyl chloride, 2-trifluoromethylbenzyl chloride,3-trifluoromethylbenzyl chloride, 4-trifluoromethylbenzyl chloride,4-t-butylbenzyl bromide, 3,4-dichlorobenzyl chloride, 2,4-dichlorobenzylchloride, 2,6-dichlorobenzyl bromide, 2,4-dimethylbenzyl chloride,2,6-dimethylbenzyl chloride, 2-fluorobenzyl bromide, 2-bromobenzylbromide, 3-trifluoromethoxybenzyl chloride, 3-iodobenzyl chloride,3-isopropyloxybenzyl bromide, 3-nitrobenzyl bromide, 2,5-dichlorobenzylchloride, 2,3-dichlorobenzyl chloride, 3,5-dichlorobenzyl chloride,3,5-dimethoxybenzyl chloride, 3-chloro-4-methoxybenzyl bromide,5-indanylmethyl chloride, 4-fluorobenzyl bromide, 3,4-difluorobenzylbromide, 3-bromobenzyl bromide, 3-cyanobenzyl bromide, 3-phenoxybenzylbromide, 3-t-butylbenzyl bromide, 3-chloro-4-fluorobenzyl bromide,3-methyl-4-nitrobenzyl bromide, 3-methoxy-4-chlorobenzyl bromide,3,5-dimethylbenzyl bromide, 3,4-methylenedioxybenzyl bromide,3-fluorobenzyl bromide, 3-vinylbenzyl bromide, 3-phenylbenzyl bromide,4-phenylbenzyl bromide, 3,4-dimethylbenzyl bromide,2-chloro-5-trifluoromethylbenzyl bromide, 3-chloro-4-methylbenzylbromide, 2-naphthylbenzyl chloride, 3-bromo-4-fluorobenzyl bromide,3-trifluoromethyl-4-fluorobenzyl bromide, 3,4-dibromobenzyl bromide,3-fluoro-4-chlorobenzyl bromide, 3-trifluoromethoxy-4-chlorobenzylbromide, 3-chloro-4-fluoromethoxybenzyl bromide, and3-trifluoromethyl-4-chlorobenzyl bromide.

(Aldehyde Compounds)

The following compounds may be mentioned as a heterocyclicaldehydederivative of formula (VI): 6-chloro-3-pyridinecarboxaldehyde,6-fluoro-3-pyridinecarboxaldehyde, 5-chloro-2-pyrazinecarboxaldehyde,4-formyl-1-methylpyrazole, 4formyl-1,3-dimethylpyrazole,4-formyl-1,3,5-trimethylpyrazole, 1-ethyl-4-formylpyrazole,2-methyl-5-pyrimidinecarboxaldehyde,2-methoxy-5-pyrimidinecarboxaldehyde,2-methylthio-5-pyrimidinecarboxaldehyde, 2-pyrrolecarboxaldehyde, and1-methyl-2-pyrrolecarboxaldehyde.

As the heterocycle-methylating agent of formula (V) containing a leavinggroup X, the C₁-C₅ alkylating agent of formula (VII) and the benzylcompound (XIII), which are materials for preparation of compounds (I) ofthe invention, there may be mentioned halides, sulfuric acid esters and(unsubstituted or substituted benzene) sulfonic acid esters.

As a suitable example of the leaving group X in these compounds, theremay be mentioned halogen atoms such as chlorine, bromine and iodine, andp-toluenesulfonyloxy group.

(Reductive Amination)

The present specification will describe the steps of three differentroutes for reductive amination.

(1) Step of Route A in Reaction Scheme (A)

Synthesis of an N-heterocyclicmethylpropylamine derivative of formula(I) from a 3-phenylpropionaldehyde derivative of formula (II) and aheterocyclicmethylamine derivative of formula (III).

(2) Step of Route B-2 in Reaction Scheme (B)

Synthesis of an N-heterocyclicmethylpropylamine derivative of formula(I) from a 3-phenylpropylamine derivative of formula (IV) and aheterocyclicaldehyde derivative of formula (VI).

(3) Step of preparing an intermediate (IV) for Synthetic Scheme (1)

Among compounds (IV),the following compounds of formula (IV) have beendescribed in the literature:

N,2-dimethyl-3-phenyl-propylamine,

N,2-dimethyl-3-(4-i-propylphenyl)-propylamine,

N-butyl-3-(4-t-butylphenyl)-2-methylpropylamine,

3-(4-t-butylphenyl)-N,2-dimethylpropylamine, and

3-(4-t-butylphenyl)-2-methyl-N-propylpropylamine.

Synthesis of a 3-phenylpropylamine derivative of formula (IV) from a3-phenylpropionaldehyde derivative of formula (II) and an aminatingagent of formula (VIII).

Such reductive amination may, for example, employ methods described inthe literature: J. Am. Chem. Soc., 93, 2897 (1971); Synthesis, 135(1975); Org. React., 4, 174 (1948); Tetrahedron Letters, 31, 5595(1990); and J. Org. Chem., 61, 3849 (1996).

It is preferably carried out using a complex hydride compound (reducingagent), such as sodium cyanoborohydride or sodium triacetoxyborohydride,as the reducing agent. In addition to these, combinations ofhydrogenation catalysts such as hydrogen gas and palladium/charcoal orRaney nickel, and formic acid, for example, can also be preferably used.

(Solvents for Reductive Amination)

The reductive amination can be carried out in a solvent or undersolvent-free conditions. For the solvents that can be used then, thosedescribed below may be mentioned: alcohols such as methanol and ethanol;ethers such as tetrahydrofuran and dioxane; halogenated hydrocarbonssuch as 1,2-dichloroethane; water and acetonitrile. One kind of thesesolvents may be used alone; or, a mixed solvent containing at least onekind of these solvents may be used.

(Conditions for Reductive Amination)

The amount of the “reducing agent” (sodium cyanoborohydride, sodiumtriacetoxyborohydride or the like) to be used in the reductive aminationdescribed above is preferably 1.0-20.0 moles, and more preferably1.0-3.0 moles, to each mole of the 3-phenylpropionaldehyde derivative offormula (II) or the heterocyclicaldehyde derivative of formula (VI). Theamount of the heterocyclicmethylamine derivative of formula (III), theaminating agent of formula (VIII) or the 3-phenylpropylamine derivativeof formula (IV) is preferably 0.5-3 moles, and more preferably 0.8-1.5moles, to each mole of compound (II) or compound (VI).

Reaction temperatures for use are those in the range of from roomtemperature to the boiling points; but 20-50° C. is preferred.

(Alkylation)

Throughout the present specification, alkylation will be referred to forillustration of:

the step of synthesizing an N-heterocyclicmethylpropylamine derivativeof formula (I) from a 3-phenylpropylamine derivative of formula (IV) anda heterocycle-methylating agent of formula (V), i.e. Route B-1 inReaction Scheme (B) as described above;

the step of synthesizing an N-alkyl-N-heterocyclicmethylpropylaminederivative of formula (I-b) [equivalent to compound (I) whereinR³=C₁-C₅] from an N-heterocyclicmethylpropylamine derivative of formula(I-a) (secondary amine) [equivalent to compound (I) wherein R³=H] and aC₁-C₅ alkylating agent of formula (VII) in Reaction Scheme (C) asdescribed above; and

the step of synthesizing a benzyl derivative of formula (X) from amethylmalonic acid diester of formula (IX) and a benzyl compound offormula (XIII), and the step of synthesizing a benzylated imino compoundof formula (XV) from an imino compound of formula (XIV) and a benzylcompound of formula (XIII) in Synthetic Scheme (2) as described above.

These steps may employ ordinary conditions for alkylation. The reactioncan be carried out either in a solvent or under solvent-free conditions.

(Solvents for Alkylation)

The following may, for example, be mentioned as solvent: hydrocarbonssuch as benzene, toluene, xylene and hexane; halogenated hydrocarbonssuch as methylene chloride, chloroform and carbon tetrachloride; etherssuch as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane;ketones such as acetone and methyl ethyl ketone; and others such asacetonitrile, dimethylformamide, 1-methyl-2-pyrrolidinone anddimethylsulfoxide.

(Bases)

From the standpoint of accelerating the alkylation described above, itis preferred that said reaction be carried out in the presence of abase. For bases that are used here, those described below may, forexample be mentioned: inorganic bases such as sodium carbonate,potassium carbonate, sodium bicarbonate, sodium hydroxide and potassiumhydroxide; the alkoxides of alkaline metals such as sodium methoxide,sodium ethoxide and potassium t-butoxide; alkaline metal hydrides suchas sodium hydride and potassium hydride; the organometallic compounds ofalkaline metals such as n-butyllithium; alkaline metal amides such aslithium diisopropylamide; and among others, organic tertiary amines suchas triethylamine, pyridine, N,N-dimethylaniline and DBU(1,8-diazabicyclo[5.4.0]undec-7-ene). Among the bases described above,the inorganic bases such as potassium carbonate and sodium carbonate areusable most preferably.

The amount of the base to be used is preferably 1.0-10.0 moles, and morepreferably 1.0-2.0 moles, to each mole of the 3-phenylpropylaminederivative of formula (IV) or the N-heterocyclicmethylpropylaminederivative of formula (I-a) (secondary amine) [equivalent to compound(I) wherein R³=H].

(Alkylating Agents)

The amount of the heterocycle-methylating agent of formula (V), theC₁-C₅ alkylating agent of formula (VII) or the benzyl compound offormula (XIII) to be used is preferably 1.0-20 moles, and morepreferably 1.0-4.0 moles, to each mole of compound (IV), compound (I-a)or compound (IX), respectively. Reaction temperatures for use duringthis alkylation are those in the range of from room temperature to theboiling points of the solvents; but 20-50° C. is preferred.

(Hydrolysis and Decarboxylation)

The hydrolysis and decarboxylation in the step of synthesizing thecarboxylic acid derivative of formula (XI) from the benzyl derivative offormula (X) in Synthetic Scheme (2) may be carried out under eitherbasic or acidic conditions.

When the reaction is carried out under basic conditions, it is preferredto use a lower alcohol or aromatic hydrocarbon in addition to water. Thebase used is preferably sodium hydroxide or potassium hydroxide. Thereaction temperature is from 40° C. to the reflux point, and preferablyfrom 70° C. to the reflux point.

When the reaction is carried out under acidic conditions, it ispreferred to use acetic acid as a solvent in addition to water. Thecatalyst used may be an inorganic acid such as hydrochloric acid orhydrobromic acid. The reaction temperature is from 50° C. to the refluxpoint, and preferably from 80° C. to the reflux point.

(Amidation)

Amidation whereby a 3-phenylpropionamide derivative of formula (XII) issynthesized from a carboxylic acid derivative of formula (XI) and anaminating agent of formula (VIII) in Synthetic Scheme (2) describedabove may be carried out by allowing a carboxylic acid derivative offormula (XI) to react with an aminating agent of formula (VIII) in thepresence of a condensation agent such as 1,3-dicyclohexylcarbodiimide(DCCD) or 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (WSCI), oralternatively by converting a carboxylic acid derivative of formula (XI)to an acid chloride by reaction with thionyl chloride, phosphorustrichloride or oxalyl chloride, and then allowing to react it with anaminating agent of formula (VIII) in the presence of a base.

(Reduction)

The reduction reaction whereby a 3-phenylpropylamine derivative offormula (IV) is synthesized from a 3-phenylpropionamide derivative offormula (XII) in Synthetic Scheme (2) described above may be carried outby allowing an amide derivative of formula (XII) to react with areducing agent such as lithium aluminum hydride or diborane. Forexample, the synthesis can be accomplished by the method described inHelv. Chim. Acta., (1948), 31, 1397 or J. Am. Chem. Soc., (1964), 86,3566.

(Hydrolysis)

The hydrolysis of a benzylated imino compound of formula (XV) to a3-phenylpropionaldehyde derivative of formula (II) is preferably carriedout under acidic conditions.

The catalyst used may be an inorganic acid such as hydrochloric acid orhydrobromic acid, or an organic acid such as acetic acid or tartaricacid. The reaction temperature is ordinarily from −10 to 50° C., andpreferably from 0 to 30° C.

The procedure is advantageously carried out by using the hydrolyzedreaction mixture directly for the reaction step of Route A, and for thisprocedure, the solvent is preferably tetrahydrofuran in combination withwater.

(Purification Treatment)

The desired compounds (I) through the above-mentioned reactions can beobtained by carrying out ordinary purification treatment aftercompletion of the reactions. More specifically, a reaction mixture asobtained from the reaction is poured into ice water. The organic layeris separated by extraction with an organic solvent such as ethylacetate, chloroform, methylene chloride or benzene. Subsequently, thisorganic layer is washed with water and dried, and then, the solvent isremoved under reduced pressure. The resulting residue is subjected tosilica gel column chromatography or the like, which enables thepurification treatment.

Optical isomers may exist for the N-heterocyclicmethylpropylaminederivative of formula (I) as obtained above, because there is anasymmetric carbon at the 2-position of its propyl group, regardless ofany asymmetry due to other substituents. In this invention, compound (I)is intended to encompass any of the single isomers alone as well asmixtures of the respective optical isomers in any desired proportion.

(Acid Addition Salts)

Since compounds (I) can readily form acid addition salts, they may beused either in the form of inorganic acid salts or in the form oforganic acid salts. For acids forming acid addition salts, there may be,for example, mentioned: inorganic acids such as hydrobromic acid,hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid; andorganic acids such as formic acid, acetic acid, butyric acid,p-toluenesulfonic acid, maleic acid, succinic acid, fumaric acid,tartaric acid, citric acid, and salicylic acid.

(Preparation Intermediates)

For 3-phenylpropylamine derivatives of formula (IV), which areintermediates that can be used in the process for preparation of thecompounds (I) of the invention as described above, there may be, forexample, mentioned the compounds listed in Table 10 below.

TABLE 10 R³ compound no. (R¹)n IV-1 methyl 4-(1,1-dimethylethyl) IV-2methyl 2-chloro 4-chloro IV-3 methyl IV-4 methyl 2,4-dichloro IV-51,1-dimethylethyl 1,1-dimethylethyl

Effective Ingredients for Agrochemicals

The compounds (I) of this invention can preferably be used as theeffective ingredients for agrochemicals. Thus, when they are to be usedas the effective ingredients for agrochemicals, the compounds (I) of theinvention per se can be used as the agrochemical, but they are normallyused, where necessary, after having been formulated together withformulating adjuvants to be used, into various forms such as dustingpowders, wettable powders, granules, and emulsifiable concentrates.

In such cases, it is preferred that the preparation be formulated so asto contain one or more compounds of the invention in an amount of 0.1-95wt % (in total), more favorably 0.5-90 wt %, and particularly 2-70 wt %,in the agrochemical preparation based on its total amount (100 wt %)which contains the compound(s) of the invention per se.

Suitable carriers, diluents and surfactants which are usable asformulating adjuvants are mentioned in the following:

Solid carriers: talc, kaolin, bentonite, diatomaceous earth, whitecarbon, clay, etc.

Liquid diluents: water, xylene, toluene, chlorobenzene, cyclohexane,cyclohexanone, dimethylsulfoxide, dimethylformamide, alcohol, etc.

Surfactants: preferably, they may be used, where appropriate, dependingon their effects. As emulsifying agents: polyoxyethylenealkyl allylethers, polyoxyethylene sorbitan monolaurate, etc. As dispersing agents:lignin sulfonate, dibutyl naphthalenesulfonate, etc. As wetting agenst:alkylsulfonates, alkylphenylsulfonates, etc.

(Dilution)

Some of the aforementioned agrochemical preparations are in the form foruse as such, and others are in the form for use after having beendiluted to their predetermined concentrations with diluents such aswater. Where the use after dilution is intended, the concentration of acompound of the invention after the dilution is preferably in the rangeof 0.001-1.0%. The use level of the compound of the invention ispreferably in the range of 20-5000 g, and more preferably 50-1000 g, perhectare (ha) of the farming or horticultural land, such as a field, ricepaddy, orchard or greenhouse.

Because these concentrations and levels for use will vary according tothe form of preparation, the period, method and location of application,the crop objects and other factors, they can be above or below theabove-mentioned ranges where necessary.

Further, the compounds of this invention may, if necessary, be used incombination with other effective ingredients such as microbicides,insecticides, miticides, herbicides and the like.

This invention will now be explained in greater detail by referring topreparation examples, reference preparation examples, formulationexamples and test examples; however, the invention is not to be limitedto the following preparation examples, formulation examples or testexamples insofar as it does not depart from the gist thereof.

EXAMPLES Preparation Example 1N-[3-(4-t-Butylphenyl)-2-methylpropyl]-6-chloro-3-pyridylmethylamine(I-3) (Indicating the Compound Number in the Tables and so ForthHereunder)

Route A: After suspending 620 mg (9.84 mmol) of sodium cyanoborohydridein 2 ml of absolute methanol, 700 mg (4.91 mmol) of6-chloro-3-pyridylmethylamine was added thereto. Subsequently, to thiswas added a solution of 1.0 g (4.90 mmol)3-(4-t-butylphenyl)-2-methylpropionaldehyde/2 ml absolute methanol byportions and then, stirring was conducted at room temperature for 4 h.

Methanol was removed under reduced pressure, water was added andextraction with methylene chloride was done. The resulting methylenechloride layer was washed with saturated brine and dried over anhydroussodium sulfate. The solvent was removed under reduced pressure and theresidue was purified with a silica gel (Silica gel 60, 230-400 mesh,Merck Co.) column [eluent composition: n-Hex (n-hexane)/AcOEt (ethylacetate)=1/1] to afford 510 mg of the desired compound (I-3) as an oil.The yield was 31.5%.

Preparation Example 2N-[3-(4-t-Butylphenyl)-2-methylpropyl]-6-chloro-N-methyl-3-pyridylmethylamine(I-4)

Method for alkylation of compound (I-a): After dissolving 170 mg (0.51mmol) ofN-[3-(4-t-butylphenyl)-2-methylpropyl]-6-chloro-3-pyridylmethylamine(I-3) in 1 ml of DMF (N,N-dimethylformamide), 163 mg (1.15 mmol) ofmethyl iodide was added thereto. Subsequently, to this was added 70 mgof sodium carbonate and stirring was conducted at room temperature for 7h and at 50° C. for 1 h.

After standing to cool, the resulting reaction solution was poured intowater and extraction with benzene was done. The benzene layer was washedwith saturated brine and dried over anhydrous sodium sulfate. Thesolvent was removed under reduced pressure and the residue was purifiedwith a silica gel (Silica gel 60, 230-400 mesh, Merck Co.) column[eluent composition: n-Hex/AcOEt=10/1] to afford 160 mg of the desiredcompound (I-4) as a colorless oil. The yield was 91.1%.

Preparation Example 36-Chloro-N-[(3-chloro-4-fluorophenyl)-2-methylpropyl]-3-pyridylmethylamine(I-70)

Route A: After dissolving 260 mg (1.30 mmol) of(3-chloro-4-fluorophenyl)-2-methylpropionaldehyde and 230 mg (1.47 mmol)of 6-chloro-N-methyl-3-pyridylmethylamine in 4 ml of anhydrous1,2-dichloroethane, 320 mg (1.51 mmol) of sodium triacetoxyborohydridewas added thereto while stirring, and stirring was continued at roomtemperature for 1 h.

Saturated sodium bicarbonate solution was added to the reaction solutionto pH 8, and extraction with methylene chloride was done. The methylenechloride layer was dried over anhydrous sodium sulfate. The solvent wasremoved under reduced pressure and the residue was purified with asilica gel (Silica gel 60, 230-400 mesh, Merck Co.) column [eluentcomposition: n-Hex/AcOEt=5/1] to afford 380 mg of the desired compound(I-70) as an oil. The yield was 85.7%.

Preparation Example 4N-[3-(4-t-Butylphenyl)-2-methylpropyl]-6-chloro-N-methyl-3-pyridylmethylamine(I-4)

Route B-1: After suspending 6.2 g (98.4 mmol) of sodium cyanoborohydridein 20 ml of absolute methanol, 6.6 g (97.8 mmol) of methylaminehydrochloride was added thereto. Subsequently, to this was added asolution of 10.0 g (49.0 mmol) 3-(4-t-butylphenyl) propionaldehyde/15 mlabsolute methanol by portions and then, stirring was conducted at roomtemperature for 9 h.

Methanol was removed under reduced pressure, water was added, the pH wasadjusted to 11 with a 2 N sodium hydroxide solution, and extraction withmethylene chloride was done. The methylene chloride layer was washedwith saturated brine and dried over anhydrous sodium sulfate. Thesolvent was removed to afford 11.2 g of an oil. This was purified with asilica gel (Wakogel C-200) column [AcOEt (for elution of impurities) andmethanol (for elution of desired product)] to afford 4.15 g of3-(4-t-butylphenyl)-N,2-dimethylpropylamine (IV-1). The yield was 38.7%.

After dissolving 500 mg (2.3 mmol) of the obtained compound (IV-1) abovein 2 ml of DMF, 330 mg (2.0 mmol) of 6-chloro-3-chloromethylpyridine wasadded. Subsequently, to this was added 320 mg of potassium carbonate andthen, stirring was conducted at room temperature for 8 h.

The reaction solution was poured into water and extraction with benzenewas done. The benzene layer was washed with saturated brine and driedover anhydrous sodium sulfate. The solvent was removed under reducedpressure to afford 890 mg of an oil. This was purified with a silica gel(Silica gel 60, 230-400 mesh, Merck Co.) column [eluent composition:n-Hex/AcOEt=10/1] to afford 700 mg of the desired compound (I-4) as acolorless oil. The yield was 89.1%.

Preparation Example 5N-[3-(4-t-Butylphenyl)-2-methylpropyl]-5-chloro-N-methyl-2-pyrazylmethylamine(I-12)

Route B-1: After dissolving 220 mg (1.0 mmol) of3-(4-t-butylphenyl)-N,2-dimethylpropylamine (IV-1) in 1.5 ml of DMF, 145mg (0.89 mmol) of 5-chloro-2-chloromethylpyrazine was added thereto.Subsequently, to this was added 140 mg of potassium carbonate andstirring was conducted at room temperature for 8 h.

The reaction solution was poured into water and extraction with benzenewas done. The benzene layer was washed with saturated brine and driedover anhydrous sodium sulfate. The solvent was removed under reducedpressure to afford 310 mg of an oil. This was purified with a silica gel(Silica gel 60, 230-400 mesh, Merck Co.) column (eluent composition:n-Hex/AcOEt=15/1) to afford 240 mg of the desired compound (I-12) as acolorless oil. The yield was 78.1%.

Preparation Example 6N-[3-(4-t-Butylphenyl)-2-methylpropyl]-N,1-dimethyl-1H-pyrazol-4-ylmethylamine(I-17)

Route B-2: After suspending 200 mg (3.2 mmol) of sodium cyanoborohydridein 2 ml of absolute methanol, 380 mg (1.7 mmol) of3-(4-t-butylphenyl)-N,2-dimethylpropylamine (IV-1) was added thereto.Subsequently, to this was added a solution of 170 mg (1.6 mmol)4-formyl-1-methylpyrazole/2 ml absolute methanol by portions, the pH wasadjusted to 7 with acetic acid, and then stirring was conducted at roomtemperature for 8 h.

Methanol was removed under reduced pressure, water was added andextraction with ethyl acetate was done. The ethyl acetate layer waswashed with saturated brine and dried over anhydrous sodium sulfate. Thesolvent was removed under reduced pressure and the residue was purifiedwith a silica gel (Silica gel 60, 230-400 mesh, Merck Co.) column(eluent composition: n-Hex/AcOEt=1/1) to afford 340 mg of the desiredcompound (I-17) as an oil. The yield was 70.1%.

The following Tables 11-21 list the types of preparation method (RouteB-1 or Route B-2) for compounds that were prepared by manipulationsfollowing Preparation Examples 1-6 with or without modifications (whenalkylation was carried out after Route A, this is also indicated), andtheir NMR data. These tables also include compound (I-3), compound(I-4), compound (I-12), compound (I-17) and compound (I-70).

TABLE 11 compound no. ¹H-NMR (δ, ppm) type of preparation method: RouteA Route B-1 Route B-2 I-1 0.85(d, 3H, J = 6 Hz), 1.27(s, 9H), Route B-11.58-3.08(m, 5H), 2.22(s, 3H), 3.58(s, 2H), 6.97(d, 2H, J = 8 Hz),6.97(d, 2H, J = 8 Hz), 7.22(d, 2H, J = 8 Hz), 6.85-7.62(m, 3H),8.32-8.53(m, 1H) I-2 0.85(d, 3H, J = 6 Hz), 1.27(s, 9H), Route B-11.70-3.00(m, 5H), 2.13(s, 3H), 3.42(s, 2H), 7.02(d, 2H, J = 8 Hz),7.22(d, 2H, J = 6 Hz), 7.25(d, 2H, J = 8 Hz), 8.48(d, 2H, J = 6 Hz) I-30.87(d, 3H, J = 6Hz), 1.25(s, 9H), Route A 1.53-2.83(m, 6H), 3.63(s,2H), 6.93(d, 2H, J = 8 Hz), 7.13(d, 1H, J = 8 Hz), 7.20(d, 2H, J = 8Hz), 7.52(dd, 1H, J = 2, 8 Hz), 8.20(d, 1H, J = 2 Hz) I-4 0.82(d, 3H, J= 6 Hz), 1.27(s, 9H), Route B-1 1.53-3.00(m, 5H), 2.13(s, 3H), 3.40(s,2H), 6.90(d, 2H, J = 8 Hz), 7.18(d, 1H, J = 8 Hz), 7.22(d, 2H, J = 8Hz), 7.57(dd, 1H, J = 2, 8 Hz), 8.22(d, 1H, J = 2 Hz) I-5 0.82(d, 3H, J= 6 Hz), 1.27(s, 9H), Route B-1 1.67-2.93(m, 5H), 2.13(s, 3H), 3.37(s,2H), 6.97(d, 2H, J = 8 Hz), 7.23(d, 2H, J = 8 Hz), 7.23-7.50(m, 2H),8.23(d, 1H, J = 2 Hz) I-6 0.83(d, 3H, J = 6 Hz), 1.27(s, 9H), Route B-11.87-3.07(m, 5H), 2.13(s, 3H), 3.40(s, 2H), 6.77(dd, 1H, J = 3, 8 Hz),6.95(d, 2H, J = 8 Hz), 7.20(d, 2H, J = 8 Hz), 7.68(ddd, 1H, J = 3, 8, 8Hz), 8.02(d, 1H, J = 3 Hz) I-7 0.83(d, 3H, J = 6 Hz), 1.27(s, 9H), RouteB-1 1.80-3.17(m, 5H), 2.12(s, 3H), 2.48(s, 3H), 3.37(s, 2H), 6.95(d, 2H,J = 8 Hz), 7.20(d, 2H, J = 8 Hz), 6.87-7.60(m, 2H), 8.33(d, 1H, J = 2Hz)

TABLE 12 compound no. ¹H-NMR (δ, ppm) type of preparation method: RouteA Route B-1 Route B-2 I-8 0.87(d, 3H, J = 6Hz), 1.28(s, 9H), Route B-11.73-3.00(m, 5H), 2.17(s, 3H), 3.52(s, 2H), 6.98(d, 2H, J = 8 Hz),7.25(d, 2H, J = 8 Hz), 7.55(d, 1H, J = 8 Hz), 7.80(dd, 1H, J = 2, 8 Hz),8.60(d, 1H, J = 2 Hz) I-9 0.85(d, 3H, J = 6 Hz), 1.30(s, 9H), Route B-11.97-3.00(m, 5H), 2.15(s, 3H), 3.37(s, 2H), 3.90(s, 3H), 6.65(d, 1H, J =8 Hz), 7.00(d, 2H, J = 8 Hz), 7.25(d, 2H, J = 8 Hz), 7.5(dd, 1H, J = 2,8 Hz), 7.97(d, 1H, J = 2 Hz) I-10 0.85(d, 3H, J = 6 Hz), 1.27(s, 9H),Route B-1 1.57-3.00(m, 5H), 2.20(s, 3H), 3.53(s, 2H), 6.98(d, 2H, J = 8Hz), 7.23(d, 2H, J = 8 Hz), 6.97-7.30(m, 1H), 7.83(dd, 1H, J = 2, 8 Hz),8.22(dd, 1H, J = 2, 5Hz) I-11 0.85(d, 3H, J = 6 Hz), 1.27(s, 9H), RouteB-1 1.50-3.00(m, 5H), 2.17(s, 3H), 3.48(s, 2H), 6.98(d, 2H, J = 8 Hz),7.18(d, 1H, J = 8 Hz), 7.25(d, 2H, J = 8Hz), 7.82(d, 1H, J = 8 Hz) I-120.82(d, 3H, J = 6 Hz), 1.25(s, 9H), Route B-1 1.65-2.92(m, 5H), 2.20(s,3H), 3.58(s, 2H), 6.95(d, 2H, J = 8 Hz), 7.20(d, 2H, J = 8 Hz), 8.40(s,2H) I-13 0.85(d, 3H, J = 6 Hz), 1.27(s, 9H), Route B-1 1.70-2.93(m, 5H),2.23(s, 3H), 2.50(s, 3H), 3.60(s, 2H), 7.00(d, 2H, J = 8 Hz), 7.23(d,2H, J = 8 Hz), 8.32(d, 1H, J = 1 Hz), 8.55(d, 1H, J = 1 Hz) I-14 0.92(d,3H, J = 6 Hz), 1.35(s, 9H), Route B-1 1.77-2.93(m, 5H), 2.3(s, 3H), 2.67 (s, 3H), 3.65(s, 2H), 7.03(d, 2H, J = 8 Hz), 7.28(d, 2H, J = 8 Hz),8.33(s, 1H) I-15 0.78(d, 3H, J = 6 Hz), 1.30(s, 9H), Route B-21.57-2.93(m, 5H), 2.12(s, 3H), 3.48(s, 2H), 3.62(s, 3H), 6.68(d, 1H, J =1 Hz), 6.78(d, 1H, J = 1 Hz), 6.90(d, 2H, J = 8 Hz), 7.17(d, 2H, J = 8Hz)

TABLE 13 compound no. ¹H-NMR (δ, ppm) type of preparation method: RouteA Route B-1 Route B-2 I-16 0.83(d, 3H, J = 6 Hz), 1.28(s, 9H), Route B-11.43-2.97(m,5H), 2.20(s, 3H), 3.77(s, 2H), 6.98(d, 2H, J = 8 Hz),7.23(d, 2H, J = 8 Hz), 7.37(d, 1H, J = 9 Hz), 7.63(d, 1H, J = 9 Hz) I-170.83(d, 3H, J = 6 Hz,), 1.28(d, 9H), Route B-2 1.98-2.98(m, 5H), 2.13(s,3H), 3.33(s, 2H), 3.78(s, 3H), 6.97(d, 2H, J = 8 Hz), 7.13(s, 1H)7.18(d, 2H, J = 8 Hz), 7.28(s, 1H) I-18 0.80(d, 3H, J = 6 Hz), 1.27(s,9H), Route B-2 1.80-2.93(m, 5H), 2.10(s, 3H), 2.20(s, 3H), 3.23(s, 2H),3.72(s, 3H), 6.97(d, 2H, J = 8 Hz), 7.05(s, 1H), 7.23(d, 2H, J = 8 Hz)I-19 0.83(d, 3H, J = 6 Hz), 1.28(s, 9H), Route B-2 1.63-2.93(m, 5H),2.13(s, 3H), 3.33(s, 2H), 3.75(s, 3H), 6.98(d, 2H, J = 8 Hz), 7.22(d,2H, J = 8 Hz), 7.32(s, 1H) I-20 0.78(d, 3H, J = 6 Hz), 1.28(s, 9H),Route B-2 1.73-2.97(m, 5H), 2.05(s, 3H), 2.15(s, 6H), 3.13(s, 2H),3.62(s, 3H, 6.93(d, 2H, J = 8 Hz), 7.18(d, 2H, J = 8 Hz) I-21 0.85(d,3H, J = 6 Hz), 1.28(s, 9H), Route B-1 1.67-2.93(m, 5H), 2.20(s, 3H),3.58(s, 2H), 7.00(d, 2H, J = 8 Hz), 7.25(d, 2H, J = 8 Hz), 7.25(s, 1H)I-22 0.85(d, 3H, J = 6 Hz), 1.28(s, 9H), Route B-1 1.62-2.95(m, 5H),2.25(s, 3H), 3.67(s, 2H), 6.02(d, 1H, J = 2 Hz), 7.00(d, 2H, J = 8 Hz),7.25(d, 2H, J = 8 Hz), 8.08(d, 1H, J = 2 Hz) I-23 0.78(d, 3H, J = 6 Hz),1.67-3.27(m, 5H), Route B-1 2.10(s, 3H), 3.35(s, 2H), 6.93-7.33(m, 4H),7.15(d, 1H, J = 8 Hz), 7.55(dd, 1H, J = 2, 8 Hz), 8.18(d, 1H, J = 2 Hz)I-24 0.82(d, 3H, J = 6 Hz), 1.63-3.08(m, 5H), Route B-1 2.15(s, 3H),3.42(s, 2H), 6.98(d, 2H, J = 8 Hz), 7.210(d, 2H, J = 8 Hz), 7.22(d, 1H,J = 8 Hz), 7.58(dd, 8.25(d, 1H, J = 2 Hz) I-25 0.82(d, 3H, J = 6 Hz),1.67-3.27(m, 5H), Route B-1 2.15(d, 3H), 3.42(s, 2H), 6.93-7.37(m, 3H),7.20(d, 1H, J = 8 Hz), 7.58(dd, 1H, J = 2, 8 Hz), 8.25(d, 1H, J = 2 Hz)

TABLE 14 compound no. ¹H-NMR (δ, ppm) type of preparation method: RouteA Route B-1 Route B-2 I-26 0.85(d, 3H, J = 6Hz), 1.28(s, 9H), Route B-11.57-3.07(m, 5H), 2.23(s, 3H), 3.58(s, 2H), 7.00(d, 2H, J = 8 Hz),7.25(d, 2H, J = 8 Hz), 6.90-7.73(m, 3H), I-27 0.80(d, 3H, J = 6 Hz),0.97(t, 3H, J = 7 Hz), Route A and 1.27(s, 9H), 1.48-2.92(m, 5H),alkylation 2.43(q, 2H, J = 7Hz), 3.43(s, 2H), 6.92(d, 2H, J = 8 Hz),7.12(d, 1H, J = 8 Hz), 7.18(d, 2H, J = 8 Hz), 7.53(dd, 1H, J = 2, 8 Hz),8.20(d, 1H, J = 2 Hz) I-28 0.78(d, 3H, J = 6 Hz), 0.98(d, 6H, J = 6 Hz),Route A and 1.28(s, 9H), 1.53-3.20(m, 6H), 3.50(s, 2H), alkylation6.97(d, 2H, J = 8 Hz), 7.23(d, 1H, J = 8 Hz), 7.27(d, 2H, J = 8 Hz),7.68(dd, 1H, J = 2, 8 Hz), 8.33(d, 1H, J = 2 Hz) I-29 0.85(d, 3H, J = 6Hz), 1.27(s, 9H), Route B-1 1.58-3.05(m, 5H), 2.20(s, 3H), 3.57(s, 2H),6.97(d, 2H, J = 8 Hz), 6.95-7.22(m, 1H), 7.22(d, 2H, J = 8 Hz), 7.47(d,1H, J = 2 Hz), 8.33(d, 1H, J = 5 Hz) I-30 0.82(d, 3H, J = 6 Hz), 1.28(s,9H), Route B-2 1.42(t, 3H, J = 7Hz), 1.90-3.10(m, 5H), 2.13(s, 3H),3.35(s, 2H), 4.05(q, 2H, J = 7 Hz), 6.98(d, 2H, J = 8 Hz), 7.17(s, 1H),7.23(d, 2H, J = 8 Hz), 7.30(s, 1H) I-31 0.73(d, 3H, J = 6 Hz), 1.02(s,9H), 1.23(s, 9H), Route B-1 1.37-1.77(m, 1H), 1.97(dd, 1H, J = 8, 13Hz), 2.37(d, 2H, J = 6 Hz), 2.73(dd, 1H, J = 4, 13 Hz), 3.55(s, 2H),6.75(d, 2H, J = 8 Hz), 7.10(d, 1H, J = 8 Hz), 7.13(d, 2H, J = 8 Hz),7.60(dd, 1H, J = 2, 8 Hz), 8.25(d, 1H, J = 2 Hz) I-32 0.85(d, 3H, J = 6Hz), 1.28(s, 9H), Route B-1 1.67-2.93(m, 5H), 2.17(s, 3H), 2.70(s, 3H),3.40(s, 2H), 7.00(d, 2H, J = 8 Hz), 7.27(d, 2H, J = 8 Hz), 8.55(s, 2H)I-33 0.85(d, 3H, J = 6 Hz), 1.27(s, 9H), Route B-1 1.87-3.10(m, 5H),2.18 (s, 3H), 3.48(s, 2H), 6.93(d, 2H, J = 8 Hz), 7.20(d, 2H, J = 8 Hz),8.57(s, 1H) I-34 0.83(d, 3H, J = 6 Hz), 1.27(s, 9H), Route B-21.58-2.92(m, 5H), 2.12(s, 3H), 3.33(s, 2H), 3.92(s, 3H), 6.95(d, 2H, J =8 Hz), 7.20(d, 2H, J = 8 Hz), 8.35(s, 2H)

TABLE 15 compound no. ¹H-NMR (δ, ppm) type of preparation method: RouteA Route B-1 Route B-2 I-35 0.85(d, 3H, J = 6 Hz), 1.27(s, 9H), Route B-21.67-3.00(m, 5H), 2.13(s, 3H), 2.53(s, 3H), 3.37(s, 2H), 6.98(d, 2H, J =8 Hz), 7.23(d, 2H, J = 8 Hz), 8.40(s, 2H) I-36 0.83(d, 3H, J = 6 Hz),1.28(s, 9H), Route B-2 1.62-2.95(m, 5H), 2.12(s, 3H), 3.42(s, 2H),5.82-6.15(m, 2H), 6.55-6.75(m, 1H), 7.00(d, 2H, J = 8 Hz), 7.25(d, 2H, J= 8 Hz) I-37 0.77(d, 3H, J = 6 Hz), 1.28(s, 9H), Route B-2 1.72-2.95(m,5H), 2.08(s, 3H), 3.32(s, 2H), 3.58(s, 3H), 5.92(d, 2H, J = 3 Hz),6.50(dd, 1H, J = 3Hz), 6.95(d, 2H, J = 8 Hz), 7.20(d, 2H, J = 8 Hz) I-380.82(d, 3H, J = 6 Hz), 1.60-3.00(m, 5H), Route A 2.13(s, 3H), 3.40(s,2H), 6.77-7.33(m, 5H), 7.58(dd, 1H, J = 2, 8 Hz), 8.25(d, 1H, J = 2 Hz)I-39 0.87(d, 3H, J = 6 Hz), 1.57-3.07(m, 5H), Route A 2.17(s, 3H),2.27(s, 3H), 3.42(s, 2H), 6.93-7.23(m, 4H), 7.20(d, 1H, J = 8 Hz),7.60(dd, 1H, J = 2, 8 Hz), 8.27(d, 1H, J = 2 Hz) I-40 0.87(d, 3H, J = 6Hz), 1.83-3.30(m, 5H), Route A 2.13(s, 3H), 3.42(s, 2H), 6.83-7.40(m,4H), 7.60(dd, 1H, J = 2, 8 Hz), 8.25(d, 1H, J = 2 Hz) I-41 0.80(d, 3H, J= 6 Hz), 1.70-3.23(m, 5H), Route A 2.13(s, 3H), 3.40(s, 2H), 3.70(s,3H), 6.60-7.33(m, 5H), 7.60(dd, 1H, J = 2, 8 Hz), 8.23(d, 1H, J = 2 Hz)I-42 0.83(d, 3H), J = 6 Hz), 1.78-3.28(m, 5H), Route A 2.13(s, 3H),3.40(s, 2H), 6.98-1.70(m, 5H), 7.58(dd, 1H, J = 2, 8 Hz), 8.22(d, 1H, J= 2 Hz) I-43 0.83(d, 3H, J = 6 Hz), 1.75-3.22(m, 5H), Route A 2.13(s,3H), 2.22(s, 3H), 2.25(s, 3H), 3.40(s, 2H), 6.78-7.08(m, 3H), 7.18(d,1H, J = 8 Hz), 7.60(dd, 1H, J = 2, 8 Hz), 8.23(d, 1H, J = 2 Hz)

TABLE 16 compound no. ¹H-NMR (δ, ppm) type of preparation method: RouteA Route B-1 Route B-2 I-44 0.83(d, 3H, J = 6 Hz), 1.67-3.17(m, 5H),Route A 2.13(s, 3H), 3.42(s, 2H), 6.67-7.25(m, 4H), 7.20(d, 1H, J = 8Hz), 7.60(dd, 1H, J = 2, 8 Hz), 8.25(d, 1H, J = 2 Hz) I-45 0.83(d, 3H, J= 6 Hz), 1.63-3.20(m, 5H), Route A 2.17(s, 3H), 3.43(s, 2H),6.93-7.47(m, 5H), 7.60(dd, 1H, J = 2, 8 Hz), 8.23(d, 1H, J = 2 Hz) I-460.82(d, 3H, J = 6 Hz), 1.77-3.27(m, 5H), Route A 2.13(s, 3H), 2.27(s,3H), 3.40(s, 2H), 6.70-7.33(m, 4H), 7.20(d, 1H, J = 8 Hz), 7.60(dd, 1H,J = 2, 8 Hz), 8.25(d, 1H, J = 2 Hz) I-47 0.87(d, 3H, J = 6 Hz), 1.25(d,6H, J = 6 Hz), Route A 1.67-3.33(m, 6H), 2.18(s, 3H), 3.45(s, 2H),6.67-7.45(m, 4H), 7.25(d, 1H, J = 8 Hz), 7.65(dd, 1H, J = 2, 8 Hz),8.32(d, 1H, J = 2 Hz) I-48 0.82(d, 3H, J = 6 Hz), 1.90-3.13(m, 5H),Route A 2.13(s, 3H), 3.40(s, 2H), 7.07-7.43(m, 5H), 7.55(dd, 1H, J = 2,8 Hz), 8.22(d, 1H, J = 2 Hz) I-49 0.80(d, 3H, J = 6 Hz), 1.63-3.00(m,5H), Route A 2.12(s, 3H), 3.38(s, 2H), 6.73-7.30(m, 4H), 7.17(d, 1H, J =8 Hz), 7.57(dd, 1H, J = 2, 8 Hz), 8.20(d, 1H, J = 2 Hz) I-50 0.80(d, 3H,J = 6 Hz), 1.53-2.90(m, 5H), Route A 2.12(s, 3H), 3.37(s, 2H),6.83-7.17(m, 2H), 7.17(d, 1H, J = 8 Hz), 7.30-7.56(m, 2H), 7.56(dd, 1H,J = 2, 8 Hz), 8.20(d, 1H, J = 2 Hz) I-51 0.82(d, 3H, J = 6 Hz), 1.27(d,6H, J = 6 Hz), Route A 1.63-2.97(m, 5H), 2.12(s, 3H), 3.37(s, 2H),4.20-4.67(m, 1H0, 6.43-6.77(m, 3H), 6.75-7.27(m, 1H), 7.15(d, 1H, J = 8Hz), 7.55(dd, 1H, J = 8 Hz), 8.20(d, 1H, J = 2 Hz) I-52 0.82(d, 3H, J =6 Hz), 1.62-3.12(m, 5H), Route A 2.17(s, 3H), 3.42(s, 2H), 7.18-7.48(m,2H), 7.20(d, 1H, J = 8 Hz), 7.60(dd, 1H, J = 2, 8 Hz), 7.75-8.10(m, 2H),8.23(d, 1H, J = 2 Hz)

TABLE 17 compound no. ¹H-NMR (δ, ppm) type of preparation method: RouteA Route B-1 Route B-2 I-53 0.84(d, 3H, J = 7Hz), 2.08-2.27(m, 4H), RouteA 2.17(s, 3H), 2.75(dd, 1H, J = 5, 14 Hz); 3.45(s, 2H), 6.62-6.70(m,3H), 7.12(t, 1H, J = 8 Hz), 7.28(d, 1H, J = 8 Hz), 7.65(dd, 1H, J = 2, 8Hz), 8.30(d, 1H, J = 2 Hz) I-54 0.82(d, 3H, J = 6 Hz), 1.50-3.08(m, 5H),Route A 2.15(s, 3H), 3.42(s, 2H), 6.88(dd, 1H, J = 2, 8 Hz), 7.18(d, 1H,J = 2 Hz), 7.22(d, 1H, J = 8 Hz), 7.27(d, 1H, J = 8 Hz), 7.58(dd, 1H, J= 2, 8 Hz), 8.25(d, 1H, J = 2 Hz) I-55 0.83(d, 3H, J = 5Hz),1.62-3.15(m, 5H), Route A 2.15(s, 3H), 3.42(s, 2H), 6.92-7.38(m, 4H),7.60(dd, 1H, J = 2, 8 Hz), 8.23(d, 1H, J = 2 Hz) I-56 0.82(d, 3H, J = 6Hz), 1.72-3.25(m, 5H), Route A 2.15(s, 3H), 3.42(s, 2H), 6.85-7.42(m,4H), 7.58(dd, 1H, J = 2, 8 Hz), 8.23(d, 1H, J = 2 Hz) I-57 0.82(d, 3H, J= 6 Hz), 1.65-3.05(m, 5H), Route A 2.13(s, 3H), 3.40(s, 2H), 6.93(d, 2H,J = 2 Hz), 7.05-7.22(m, 1H), 7.18(d, 1H, J = 8 Hz), 7.57(dd, 1H, J = 2,8 Hz), 8.23(d, 1H, J = 2 Hz) I-58 0.83(d, 3H, J = 6 Hz), 1.77-2.90(m,5H), Route A 2.12(s, 3H), 3.38(s, 2H), 3.70(s, 6H), 6.23(s, 3H), 7.20(d,1H, J = 8 Hz), 7.58(dd, 1H, J = 2, 8 Hz), 8.23(d, 1H, J = 2 Hz) I-590.80(d, 3H, J = 6 Hz), 1.85-2.92(m, 5H), Route A 2.12(s, 3H), 3.37(s,2H), 3.78(s, 3H), 6.70(d, 1H, 9 Hz), 6.92(dd, 1H, J = 2, 9 Hz), 7.07(d,1H, J = 2 Hz), 7.18(d, 1H, J = 8 Hz), 7.57(dd, 1H, J = 2, 8 Hz), 8.22(d,1H, J = 2 Hz) I-60 0.82(d, 3H, J = 6 Hz), 1.82-2.88(m, 5H), Route A2.13(s, 3H), 3.40(s, 2H), 4.32(bs, 1H), 6.78-7.37(m, 3H), 7.22(d, 1H, J= 8 Hz), 7.60(dd, 1H, J = 2, 8 Hz), 8.25(d, 1H, J = 2 Hz)

TABLE 18 compound no. ¹H-NMR (δ, ppm) type of preparation method: RouteA Route B-1 Route B-2 I-61 0.82(d, 3H, J = 6 Hz), 1.70-2.97(m, 5H),Route A 2.12(s, 3H), 3.37(s, 2H), 6.83-7.33(m, 6H), 7.55(dd, 1H, J = 2,8 Hz), 8.20(d, 1H, J = 2 Hz) I-62 0.82(d, 3H, J = 6 Hz), 1.75-3.05(m,5H), Route A 2.12(s, 3H), 3.42(s, 2H), 6.78-7.27(m, 4H), 7.22(d, 1H, J =8 Hz), 7.60(dd, 1H, J = 2, 8 Hz), 8.27(d, 1H, J = 2 Hz) I-63 0.82(d, 3H,J = 6 Hz), 1.77-3.10(m, 5H), Route A 2.15(s, 3H), 3.42(s, 2H), 7.17(d,2H, J = 8 Hz), 7.22(d, 1H, J = 8 Hz), 7.48(d, 2H, J = 8 Hz), 7.58(dd,1H, J = 2, 8 Hz), 8.27(d, 1H, J = 2 Hz) I-64 0.80(d, 3H, J = 6 Hz),1.87-2.95(m, 5H), Route A 2.15(s, 3H), 3.40(s, 2H), 6.58-7.25(m, 3H),7.20(d, 1H, J = 8 Hz), 7.58(dd, 1H, J = 2, 8 Hz), 8.25(d, 1H, J = 2 Hz)I-65 0.80(d, 3H, J = 6 Hz), 1.53-2.93(m, 5H), Route A 2.10(s, 3H),3.35(s, 2H), 6.78-7.33(m, 5H), 7.50(dd, 1H, J = 2, 8 Hz), 8.13(d, 1H, J= 2 Hz) I-66 0.82(d, 3H, J = 7 Hz), 1.63-3.10(m, 5H), Route A 2.13(s,3H), 2.27(s, 3H), 3.38(s, 2H), 6.67-7.17(m, 4H), 7.13(d, 1H, J = 8 Hz),7.53(dd, 1H, J = 2, 8 Hz), 8.18(d, 1H, J = 2 Hz) I-67 0.80(d, 3H, J = 6Hz), 1.67-3.03(m, 5H), Route A 2.13(s, 3H), 3.37(s, 2H), 7.07-7.43(m,6H), 7.55(dd, 1H, J = 2, 8 Hz), 8.20(d, 1H, J = 2 Hz) I-68 0.82(d, 3H, J= 6 Hz), 1.60-2.93(m, 5H), Route A 2.10(s, 3H), 3.37(s, 2H),6.60-7.43(m, 10H), 7.55(dd, 1H, J = 2, 8 Hz), 8.22(d, 1H, J = 2 Hz) I-690.82(d, 3H, J = 6 Hz), 1.27(s, 9H), Route A 1.53-3.00(m, 5H), 2.12(s,3H), 3.38(s, 2H), 6.70-7.30(m, 5H), 7.55(dd, 1H, J = 2, 8 Hz), 8.20(d,1H, J = 2 Hz) I-70 0.80(d, 3H, J = 6 Hz), 1.68-2.93(m, 5H), Route A2.13(s, 3H), 3.38(s, 2H), 6.67-7.05(m, 3H), 7.15(d, 1H, J = 8 Hz),7.52(dd, 1H, J = 2, 8 Hz), 8.18(d, 1H, J = 2 Hz)

TABLE 19 compound no. ¹H-NMR (δ, ppm) type of preparation method: RouteA Route B-1 Route B-2 I-71 0.82(d, 3H, J = 6 Hz), 1.50-3.27(m, 5H),Route A 2.17(s, 3H), 2.53(s, 3H), 3.42(s, 2H), 6.83-7.33(m, 3H.),7.55(dd, 1H, J = 2, 8 Hz), 7.82(d, 1H, J = 8 Hz), 8.22(d, 1H, J = 2 Hz)I-72 0.82(d, 3H, J = 6 Hz), 1.58-3.02(m, 5H), Route A 2.13(s, 3H),3.38(s, 2H), 3.78(s, 3H), 6.42-6.75(m, 2H), 7.03-7.32(m, 2H), 7.53(dd,1H, J = 2, 8 Hz), 8.20(d, 1H, J = 2 Hz) I-73 0.80(d, 3H, J = 6 Hz),1.60-3.07(m, 5H), Route A 2.12(s, 3H), 3.37(s, 2H), 3.93(bs, 1H),6.50(dd, 1H, J = 2, 8 Hz), 6.70(d, 1H, J = 2 Hz), 7.08(d, 1H, J = 8 Hz),7.17(d, 1H, J = 8 Hz), 7.53(dd, 1H, J = 2, 8 Hz), 8.18(d, 1H, J = 2 Hz)I-74 0.83(d, 3H, J = 6 Hz), 1.67-2.90(m, 5H), Route A 2.13(s, 3H),2.23(s, 6H), 3.38(s, 2H), 6.55-6.80(m, 3H), 7.15(d, 1H, J = 8 Hz),7.55(dd, 1H, J = 2, 8 Hz), 8.20(d, 1H, J = 2 Hz) I-75 0.80(d, 3H, J = 6Hz), 1.60-3.00(m, 5H), Route A 2.17(s, 3H), 3.37(s, 2H), 6.50-7.30(m,5H), 7.52(dd, 1H, J = 2, 8 Hz), 8.18(d, 1H, J = 2 Hz) I-76 0.83(d, 3H, J= 6 Hz), 1.70-3.10(m, 5H), Route A 2.13(s, 3H), 3.38(s, 2H), 3.71(s,3H), 6.50-6.80(m, 3H), 6.90-7.30(m, 2H), 7.55(dd, 1H, J = 2, 8 Hz),8.20(d, 1H, J = 2 Hz) I-77 0.80(d, 3H, J = 6 Hz), 1.60-3.20(m, 5H),Route A 2.13(s, 3H), 3.38(s, 2H), 5.10-5.50(m, 2H), 6.60-7.70(m, 7H),8.24(d, 1H, J = 2 Hz) I-78 0.85(d, 3H, J = 6 Hz), 1.70-3.10(m, 5H),Route A 2.12(s, 3H), 3.35(s, 2H), 6.80-7.90(m, 11H), 8.22(d, 1H, J = 2Hz) I-79 0.83(d, 3H, J = 6 Hz), 1.80-3.10(m, 5H), Route A 2.10(s, 3H),3.35(s, 2H), 6.90-7.60(m, 11H), 8.12(d, 1H, J = 2 Hz)

TABLE 20 compound no. ¹H-NMR (δ, ppm) type of preparation method: RouteA Route B-1 Route B-2 I-80 0.82(d, 3H, J = 6 Hz), 1.80-2.90(m, 5H),Route A 2.10(s, 3H), 2.16(s, 6H), 3.35(s, 2H), 6.60-7.20(m, 4H),7.53(dd, 1H, J = 2, 8 Hz), 8.18(d, 1H, J = 2 Hz) I-81 0.82(d, 3H, J = 6Hz), 1.60-3.20(m, 5H), Route A 2.16(s, 3H), 3.43(s, 2H), 7.10-7.70(m,5H), 8.24(d, 1H, J = 2 Hz) I-82 0.80(d, 3H, J = 6 Hz), 1.70-2.90(m, 5H),Route A 2.12(s, 3H), 2.27(s, 3H), 3.38(s, 2H), 6.70-7.30(m, 4H),7.55(dd, 1H, J = 2, 8 Hz), 8.22(d, 1H, J = 2 Hz) I-83 0.80(d, 3H, J = 6Hz), 1.68-2.95(m, 5H), Route A 2.13(s, 3H), 3.40(s, 2H), 6.74-7.33(m,4H), 7.56(dd, 1H, J = 2, 8 Hz), 8.23(d, 1H, J = 2 Hz) I-84 0.80(d, 3H, J= 6 Hz), 1.65-3.02(m, 5H), Route A 2.13(s, 3H), 3.40(s, 2H),6.75-7.42(m, 3H), 7.17(d, 1H, J = 8 Hz), 7.57(dd, 1H, J = 2, 8 Hz),8.22(d, 1H, J = 2 Hz) I-85 0.80(d, 3H, J = 6 Hz), 1.58-2.95(m, 5H),Route A 2.12(s, 3H), 3.38(s, 2H), 6.82(dd, 1H, J = 2, 8 Hz),7.08-7.72(m, 4H), 8.22(d, 1H, J = 2 Hz) I-86 0.82(d, 3H, J = 6 Hz),1.63-2.97(m, 5H), Route A 2.13(s, 3H), 3.42(s, 2H), 6.67-7.40(m, 3H),7.22(d, 1H, J = 8 Hz), 7.60(dd, 1H, J = 2, 8 Hz), 8.27(d, 1H, J = 2 Hz)I-87 0.82(d, 3H, J = 6 Hz), 1.77-3.27(m, 5H), Route A 2.13(s, 3H),3.40(s, 2H), 4.27(q, 2H, J = 8 Hz), 6.50-6.87(m, 3H), 7.00-7.37(m, 2H),7.58(dd, 1H, J = 2, 8 Hz), 8.27(d, 1H, J = 2 Hz)

TABLE 21 compound no. ¹H-NMR (δ, ppm) type of preparation method: RouteA Route B-1 Route B-2 I-90 0.83(d, 3H, J = 6 Hz), 1.55-2.42(m, 6H),Route A 2.13(s, 3H), 2.52-3.02(m, 5H), 3.38(s, 2H), 6.63-7.18(m, 3H),7.17(d, 1H, J = 8 Hz), 7.57(dd, 1H, J = 2, 8 Hz), 8.23(d, 1H, J = 2 Hz)I-91 0.80(d, 3H, J = 6 Hz), 1.25-2.88(m, 5H), Route A 2.12(s, 3H),3.37(s, 2H), 5.80(s, 2H), 6.28-6.82(m, 3H), 7.15(d, 1H, J = 8 Hz),7.53(dd, 1H, J = 2, 8 Hz), 8.17(d, 1H, J = 2 Hz) I-92 0.85(d, 3H, J = 6Hz), 1.80-3.10(m, 5H), Route A 2.12(s, 3H), 3.35(s, 2H), 7.00-7.80(m,9H), 8.23(d, 1H, J = 2 Hz)

Table 22 shows the NMR data for a few 3-phenylpropylamine derivatives(IV) to be used as starting compounds for the preparation of compounds(I) by Route B-1 and Route B-2.

TABLE 22 compound no. ¹H-NMR (δ, ppm) IV-2 0.88(d, 3H, J = 6 Hz),1.63(s, 1H), 1.72-3.32(m, 5H), 2.37(s, 3H), 6.93-7.43(m, 4H) IV-30.87(d, 3H, J = 6 Hz), 1.40-3.23(m, 5H), 2.42(s, 3H), 4.38(s, 1H),7.00(d, 2H, J = 8 Hz), 7.20(d, 2H, J = 8 Hz) IV-4 0.87(d, 3H, J = 6 Hz),1.17(s, 1H), 1.58-3.17(m, 5H), 2.37(s, 3H), 7.17-7.33(m, 3H)

Formulation Example 1 Dusting Powder Formulation

The following ingredients were pulverized and blended for use as adusting powder.

Parts by Weight Compound (I-4) 3 Clay 40 Talc 57

Formulation Example 2 Wettable Powder Formulation

The following ingredients were pulverized and blended into a wettablepowder, and diluted with water for use.

Parts by weight compound (I-12) 50 Lignin sulfonate 5 Alkylsulfonate 3Diatomaceous earth 42

Formulation Example 3 Granule Formulation

The following ingredients were uniformly blended, combined with water,kneaded and then processed and dried into granular form with anextruder-type granulator, to prepare granules.

Parts by weight Compound (I-17) 5 Bentonite 43 Clay 45 Lignin sulfonate7

Formulation Example 4 Emulsifiable Concentrate Formulation

The following ingredients were uniformly blended and dissolved toprepare an emulsifiable concentrate.

Parts by Weight Compound (I-4) 20 Polyoxyethylenealkyl allyl ether 10Polyoxyethylene sorbitan monolaurate 3 Xylene 67

Test Example 1 Test of Controlling Effect on Wheat Powdery Mildew

Seeslings of wheat (variety: “Abukumawase”) at the first to second leafperiod were cultivated using square plastic pots (size: 6.4 cm×6.4 cm).Such a wettable powder form as obtained in Formulation Example 2 wasdiluted and suspended with water to provide the prescribed concentration(500 mg/l), and was sprinkled onto wheat at a level of 100 liters/10 a(ares).

After air-drying the sprinkled leaves, a suspension of wheat powderymildew spores taken from infected leaves was inoculated by spraying ontothe air-dried sprinkled leaves. They were maintained under highly humidconditions at 20-24° C. for 24 h, and then supervised in a green house(temperature: 20-24° C., relative humidity: 20-70 RH). On the 9th to14th days after inoculation, the infection degree was examined accordingto the following scale and the control value was calculated as shownbelow (Equation 1).

(Examination Scale) Infection degree Severity 0 No infection 0.5 Lesionarea proportion: less than 1% 1 Lesion area proportion: 1% to less than5% 2 Lesion area proportion: 5% to less than 10% 3 Lesion areaproportion: 10% to less than 30% 4 Lesion area proportion: 30% to lessthan 50% 5 Lesion area proportion: 50% or more

 Control value (%)=(1−infection degree of treated zone/infection degreeof untreated zone)×100  (Equation 1)

The results thus obtained above are shown in Tables 23-24 below.

TABLE 23 compound control no. value I-1 83 I-3 100 I-4 100 I-6 98 I-7100 I-8 100 I-9 100 I-12 100 I-13 80 I-14 100 I-17 98 I-19 97 I-23 100I-24 100 I-25 100 I-26 83 I-27 98 I-30 100 I-34 80 I-38 100 I-39 100I-40 100 I-41 88 I-42 100 I-43 100 I-44 98 I-45 100 I-46 100 I-47 100I-48 100 I-49 100 I-50 100

TABLE 24 compound control no. value I-51 98 I-52 90 I-54 100 I-55 98I-56 100 I-57 100 I-58 80 I-59 100 I-61 100 I-63 100 I-64 100 I-65 100I-69 100 I-70 100 I-74 98 I-75 70 I-77 100 I-79 80 I-80 70 I-81 100 I-82100 I-90 70

Test Example 2 Test of Controlling Effect on Cucumber Powdery Mildew

Cucumber (variety: “Sagamihanpakufushinari”) at the first to second leafperiod was cultivated using square plastic pots (size: 6.4 cm×6.4 cm).Such a wettable powder form as obtained in Formulation Example 2 wasdiluted and suspended with water to provide the prescribed concentration(250 mg/l), and it was sprinkled onto the cucumber at a level of 100liters/10

a. After air-drying the sprinkled leaves, spores taken from infectedleaves were inoculated by dispersing with a brush onto the air-driedsprinkled leaves. An outbreak of the disease was allowed to occur in aglass green house (temperature: 20-24° C., relative humidity: 20-70 RH).On the 9th to 14th days after inoculation, the infection degree wasexamined according to the following scale and the control value wascalculated as shown below (Equation 2).

(Examination scale) Infection degree Severity 0 No infection 0.5 Lesionarea proportion: less than 5% 1 Lesion area proportion: 5% to less than10% 2 Lesion area proportion: 10% to less than 30% 3 Lesion areaproportion: 30% to less than 50% 4 Lesion area proportion: 50% to lessthan 70% 5 Lesion area proportion: 70% or more

 Control value (%)=(1−infection degree of treated zone/infection degreeof untreated group)×100  (Equation 2)

The results thus obtained above are shown in Table 25 below.

TABLE 25 compound control no. value I-4 98 I-5 100 I-6 100 I-7 100 I-8100 I-9 98 I-12 100 I-22 90 I-25 98 I-48 100 I-49 100 I-50 100 I-54 100I-55 100 I-57 100 I-59 100 I-65 100 I-69 100 I-78 100 I-79 100 I-80 100I-92 100

Test Example 3 Antifungal Activity Test against Various Pathogenic Fungi

In the test example, the antifungal activity of compounds of thisinvention was tested against various plant pathogenic fungi according tothe method which will be descibed hereunder.

(Test Method)

Each 10 mg of a compound of the invention was weighed and dissolved in 1ml of dimethyl sulfoxide. A 0.6 ml portion of the solution was added to60 ml of PDA medium (potato-dextrose-agar medium) at about 60° C., andit was thoroughly mixed in a 100-ml Erlenmeyer flask and then pouredinto a petri dish to solidify to prepare a plate medium containing thecompound of the invention at a final concentration of 100 mg/l.

Next, test fungi that had been precultured in a plate medium werepunched out with a cork bowler of 4-mm diameter and seeded on thechemical-containing plate medium described above. After seeding, eachfungi was cultured for 1-3 days at its optimum growth temperature (Theoptimum growth temperatures may be found, for example, by reference tothe publication “LIST OF CULTURES, 1996 Microorganisms, 10th Edition,The Fermentation Research Institute (Foundation).” The growth of fungiwas measured in terms of its colony diameter. In this way, the growthlevel of each of the fungi resulting on the chemical-containing platemedium was compared with the growth level of the same fungi in achemical-free group, and the percent inhibition of hypha elongation wasdetermined according to the following equation 3:

R=100(dc−dt)/dc  (Equation 3)

wherein “R” represents hypha elongation inhibition (%), “dc” representsthe colony diameter on non-treated plate medium, and “dt” represents thecolony diameter on chemical-treated plate medium, respectively.

The results obtained as described above were evaluated at five levelsaccording to the following scale.

Growth Inhibition

5: Hypha elongation inhibition of 90% or more

4: Hypha elongation inhibition of from 70% to less than 90%

3: Hypha elongation inhibition of from 40% to less than 70%

2: Hypha elongation inhibition of from 20% to less than 40%

1: Hypha elongation inhibition of less than 20%

The evaluation results thus obtained are shown in Table 26 below.

TABLE 26 compound test fungi no. B. c. M. f. F. niv. P. c. I-4 5 5 5 5I-5 5 5 4 4 I-6 5 5 5 4 I-8 5 5 5 4 I-9 5 5 5 5 I-12 5 5 5 4 I-13 5 5 54 I-14 5 5 4 3 I-16 4 5 4 5 I-22 5 5 5 5 The following compoundsexhibited level 5 inhibition against gray mold. I-39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 54, 55, 56, 57, 58, 59, 61, 65, 66, 68,69, 70, 72, 74, 75, 76, 77, 78, 79, 80, 81, 82, 90, 92

The meanings of the abbreviations in Table 26 above are as follows.

B.c.: Botrytis cinerea (Gray mold)

M.f.: Monilinia fructicola (Brown rot mold-peaches)

F.niv.: Fusarium nivale (Fusarium blight mold-wheat)

P.c.: Phytophthora capsici (Gray disease mold-cucumber)

Industrial Applicability

As explained above, this invention provides anN-heterocyclicmethylpropylamine derivative of formula (I):

or an acid addition salt thereof;

wherein R¹ represents at least one moiety selected from the groupconsisting of hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆halogenated alkyl, C₁-C₆ alkoxy, C₁-C₆ halogenated alkoxy, hydroxyl,cyano, nitro, phenyl optionally having a substituent on a ring thereofand phenoxy; n represents an integer of 0-5; when n is 2 or greater,each R¹ may be the same or different and two R¹ groups may be bondedtogether into a ring or crosslinked; R² represents a heterocyclecontaining at least one nitrogen atom as the hetero atom and optionallyhaving a substituent on a ring thereof; and R³ represents at least onemoiety selected from the group consisting of hydrogen and C₁-C₅ alkyl.

The invention further provides a process for preparation comprisingreductive amination between a 3-phenylpropionaldehyde derivative offormula (II) and a heterocyclicmethylamine derivative of formula (III)to obtain an N-heterocyclicmethylpropylamine derivative of formula (I):

(in formulae (I), (II) and (III) R¹, R², R³ and n are as previouslydefined).

The invention still further provides the following preparationprocesses.

A process for preparation comprising alkylation between a3-phenylpropylamine derivative of formula (IV) and aheterocycle-methylating agent of formula (V) to obtain anN-heterocyclicmethylpropylamine derivative of formula (I):

(in formulae (I), (IV) and (V) R¹, R², R³ and n are as defined above,and X represents a leaving group).

A process for preparation comprising reductive amination between a3-phenylpropylamine derivative of formula (IV) and aheterocyclicaldehyde derivative of formula (VI) to obtain anN-heterocyclicmethylpropylamine derivative of formula (I):

(in formulae (I), (IV) and (VI) R¹, R², R³ and n are as previouslydefined).

The invention still further provides a fungicide containing anN-heterocyclicmethylpropylamine derivative of formula (I) or an acidaddition salt thereof as the effective ingredient:

wherein R¹, R², R³ and n are as previously defined.

The novel N-heterocyclicmethylpropylamine derivatives of the inventionand their acid addition salts can most effectively be used as, e.g.,such fungicides for farming and horticulture as stated above against avariety of pathogenic fungi.

What is claimed is:
 1. An N-heterocyclicmethylpropylamine derivative offormula (I):

or an acid addition salt thereof; wherein R¹ represents a moietyselected from the group consisting of hydrogen, halogen, C₁-C₆ alkyl,C₁-C₆ alkenyl, C₁-C₆ halogenated alkyl, C₁-C₆ alkoxy, C₁-C₆ halogenatedalkoxy, hydroxyl, cyano, nitro, phenyl optionnally having a substituenton a ring thereof and phenoxy; n represents an integer of 0-5; when n is2 or greater, each R¹ may be the same or different and two R¹ groups maybe bonded together to form a ring selected from a group consisting ofindane, 1,2-methylenedioxybenzene and naphthalene; R² represents aheterocycle selected from a group consisting of pyridine, pyrazine,pyrimidine, thiazole, oxazole, pyrazole and pyrrole, said heterocycleoptionally having a substituent on a ring thereof; and R³ represents amoiety selected from the group consisting of hydrogen and C₁-C₅ alkyl,with the proviso that the following compounds are excluded:N-[3-(4-t-butylphenyl)-2-methylpropyl]-N-(t-butyl)-3-pyridylmethylamine,N-[3-(4-t-butylphenyl)-2-methylpropyl]-N-butyl-3-pyridylmethylamine, andN-[3-(4-t-butylphenyl)-2-methylpropyl]-N-methyl-3-pyridylmethylamine. 2.A fungicide compound containing as an effective ingredient, anN-heterocyclicmethylpropylamine derivative of formula (I):

or an acid addition salt thereof; wherein R¹ represents a moietyselected from the group consisting of hydrogen, halogen, C₁-C₆ alkyl,C₁-C₆ alkenyl, C₁-C₆ halogenated alkyl, C₁-C₆ alkoxy, C₁-C₆ halogenatedalkoxy, hydroxyl, cyano, nitro, phenyl optionally having a substituenton a ring thereof and phenoxy; n represents an integer of 0-5; when n is2 or greater, each R¹ may be the same or different and two R¹ groups maybe bonded together to form a ring selected from a group consisting ofindane, 1,2-methylenedioxybenzene and naphthalene; R² represents aheterocycle selected from a group consisting of pyridine, pyrazine,pyrimidine, thiazole, oxazole, pyrazole and pyrrole, said heterocycleoptionally having a substituent on a thereof; and R³ represents a moietyselected from the group consisting of hydrogen and C₁-C₅ alkyl, with theproviso that the following compounds are excluded:N-[3-(4-t-butylphenyl)-2-methylpropyl]-N-(t-butyl)-3-pyridylmethylamine,N-[3-(4-t-butylphenyl)-2-methylpropyl]-N-butyl-3-pyridylmethylamine, andN-[3-(4-t-butylphenyl)-2-methylpropyl]-N-methyl-3-pyridylmethylamine.